The present disclosure relates generally to methods for restoring hemostasis in bleeding disorders. More particularly, the present disclosure relates to a method for treating bleeding disorders, and in particular, hemophilia, by administering to a subject in need thereof an antibody that specifically binds CD73. In some embodiments, the methods further include administration of the combination of the antibody that specifically binds CD73 and Factor VIII.
Platelets (or thrombocytes) are small, irregularly shaped cell fragments derived from megakaryocytes that circulate in the blood of mammals and participate in hemostasis. In normal hemostasis, endothelial cells that line the inner surface of blood vessels prevent platelet activation by producing nitric oxide, endothelial-ADPase and PGI2. When the endothelial layer is injured, collagen, von Willebrand factor (vWF) and tissue factor from the subendothelium is exposed to the bloodstream. When the platelets contact collagen or vWF, they are activated, which is a critical component in the formation of a blood clot (thrombosis) to prevent blood loss. When hemostasis is hindered, however, thrombosis is slowed or even prevented, leading to severe loss of blood.
Conventionally, treatment efforts for abnormal hemostasis, such as found in subjects with bleeding disorders (e.g., hemophilia, von Willebrand Disease, etc.) or suffering severe trauma, have focused on the activation of the coagulation cascade system. The coagulation cascade system, shown in FIG. 1, involves two initial pathways, the extrinsic pathway and the intrinsic pathway. The extrinsic pathway involves tissue factor and Factor VII complex to activate Factor X, while the intrinsic pathway involves high-molecular weight kininogen, prekallikrein, and Factors XII, XI, IX and VIII to activate Factor X. Both the extrinsic and intrinsic pathways lead to a final common pathway in which Factor X mediates the generation of thrombin from prothrombin, with the ultimate production of fibrin from fibrinogen.
Platelets and endothelial cells also play important roles in hemostasis, and therefore, in bleeding disorders, it is now believed that normal hemostasis could potentially further be restored by modulating platelet and endothelial cell activities. More particularly, it is now believed that platelet activation and coagulation can be increased at the surface of endothelial cells, thereby generating a pro-hemostatic effect.
While treatments of bleeding disorders through the use of modulating/enhancing the coagulation cascade system have met with success, there exists a need to develop alternative mechanisms to restore hemostasis. Particularly, methods for activating platelets and increasing platelet surface coagulation at the site of endothelial cells themselves could prove advantageous in treating bleeding disorders. These methods alone, or in combination with conventional pro-coagulation cascade treatments, may provide for more efficient and effective generation of pro-hemostatic effects in subjects suffering from bleeding disorders and in other bleeding situations.